Beta-catenin (β-catenin) is a member of the plakophilin protein family. The plakophilins belong to the armadillo-related proteins, which are components of the desmosomal plaque. In addition to their adhesive function, the plakophilin β-catenins have been ascribed an important signaling function. For instance, β-catenin is a transcriptional co-activator of the T cell factor/lymphoid enhancer factor (TCF/LEF) complex that regulates embryonic, postnatal, and oncogenic growth in many tissues, including the heart (Brembeck et al. Curr Opin Genet Dev. 2006; 16:51-59).
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Cardiomyocyte growth occurs during left ventricular (LV) remodeling following chronic pressure overload and/or ischemic heart disease. Increased β-catenin levels were detected in the intercalated disc in heart specimens from patients with inherited cardiac hypertrophy (Masuelli et al. Cardiovasc Res. 2003; 60:376-387).
The β-catenin increase at the cell membrane was accompanied by reduced nuclear β-catenin levels.
LV remodeling includes re-activation of the fetal gene program and possibly the embryonic gene program as well (Liang et al. J Mol Cell Cardiol. 2002; 34:611-616). WNT/β-catenin regulation is one of the earliest events in cardiac development. Specifically, β-catenin downregulation following inhibitory Dickkopf signaling in the embryonic endoderm precedes cardiac development from the embryonic mesoderm (Lickert et al. Dev Cell. 2002; 3:171-181). Since universal β-catenin deletion is lethal, inducible tissue-specific modulation of β-catenin has been used to analyze the role of this factor in adult heart LV remodeling.
Two more recent publications have analyzed the effect of β-catenin depletion in the adult heart: Zhou et al. (Am J Physio/Heart Circ Physiol. 2007; 38:120) found no phenotype concerning membrane function due to the compensatory upregulation of plakoglobin in the intercalated disc as previously described in other tissues (Huelsken et al. Cell. 2001; 105:533-545). Chen et al. (Mol. Cell. Biol. 2006; 26:4462-4473) confirmed their previous in vitro observations concerning β-catenin in adult cardiac hypertrophy: the increase in heart weight/body weight after trans-aortic constriction was attenuated in β-catenin depleted transgenic mice.
WO 2004/094610 A2 discloses a system, method and compositions related to cardiomyocyte differentiation from a non-cardiomyocyte cell using factors that activate WNT/β-catenin-signaling. The invention is said to relate to a cell-therapy system, in which a cell the WNT/β-catenin signaling pathway is activated and this cell or a cell tissue resulting from this cell is used for the therapy of cardiac failure.
The report of Barandon et al. (Circulation 2003; 108:2282-2289) investigates the role of the soluble Frizzled related protein A, sFRP A, as a regulator of healing processes after myocardiac infarction. Generally, soluble frizzled related proteins are able to inhibit WNT-signaling with its downstream target β-catenin. By overexpressing sFRP A in transgenic mice they demonstrated that cardiac function is improved. Although this report shows a correlation between overexpression of sFRP A and a decrease of cytosolic β-catenin after myocardiac infarction, the authors are not able to directly trace back the improvement of cardiac function to the decrease of cytosolic β-catenin. The only conclusion that could be drawn from this study is that blocking WNT-signaling by sFRP A results in reduced infarct size and cardiac rupture. No conclusion about the role of β-catenin can be drawn as many different factors upstream of β-catenin are involved in WNT-signaling and may contribute to the observed effect. Furthermore WNT-dependent signaling can involve other, alternative mediators (Liu et al. Cell 2002; 108:837-847). Thus, no link has been established to the role of β-catenin in enhancing endogenous cardiac regeneration. In their discussion the authors conclude that the effect of overexpressing sFRP A is independent from β-catenin.
In sum, the exact role of β-catenin in adult cardiac remodeling in vivo is still not understood: It is unclear, which effect the modulation of β-catenin expression in the heart has and which mechanism might be involved.
Thus, there remains a need to provide alternative methods and agents for the targeted and/or specific treatment of cardiovascular diseases or disorders, especially by cardiac regeneration. There is in particular a need for treating heart failure syndrome(s).
There is also a need to provide a heart medication for the specific treatment of cardiovascular diseases or disorders.